An Antibody-Oligonucleotide Conjugate for Myotonic Dystrophy Type 1

Area of Science:

• Neuromuscular Disorders
• RNA Therapeutics
• Genetic Medicine

Background:

• Myotonic dystrophy type 1 (DM1) is a progressive, inherited neuromuscular disease with no current therapies.
• DM1 results from a trinucleotide repeat expansion in DMPK mRNA, causing toxic gain of function and alternative splicing defects.
• Delpacibart etedesiran (del-desiran) is an investigational therapy targeting DMPK mRNA.

Purpose of the Study:

• To evaluate the safety, pharmacokinetics, and pharmacodynamics of delpacibart etedesiran in patients with DM1.
• To assess the effect of del-desiran on aberrant alternative splicing patterns in DM1.

Main Methods:

• A phase 1-2, multicenter, double-blind, randomized, placebo-controlled trial was conducted.
• Participants received single or multiple intravenous doses of del-desiran (1-4 mg/kg) or placebo.
• Safety, pharmacokinetic/pharmacodynamic profiles, and changes in splicing scores were assessed.

Main Results:

• Del-desiran treatment led to significant reductions in DMPK mRNA levels in muscle biopsies.
• Reductions in missplicing scores were observed, particularly in the 2-mg and 4-mg groups.
• Mild to moderate adverse events were common; two serious adverse events were reported.

Conclusions:

• Del-desiran demonstrated muscle delivery and amelioration of aberrant splicing in DM1 patients.
• The observed safety profile and efficacy support further clinical investigation of del-desiran.
• Two serious adverse events were noted, warranting careful monitoring in future trials.